Base Model of Shp2 Regulation from Barua, Faeder, and Haugh (2006)

# Base model of Shp2 regulation from Barua, Faeder, and Haugh (2006).

# Copyright 2006, North Carolina State University and Los Alamos National

# Laboratory

# Concentration units are in micromolar; time units are in seconds.

version("2.0.34");

begin parameters

kopen 10

kclose 500

kon_CSH2 1

koff_CSH2 1

kon_NSH2 1

koff_NSH2 1

kkin_Y1 0.1

kon_PTP 1

koff_PTP 10

kcat_PTP 1

chi_r1 1000

chi_r2 100

chi_r3 1000

chi_r4 1000

chi_r5 100

chi_r6 100

chi_r7 100

chi_r8 1000 # Equals chi_r1*chi_r6/chi_r2

chi_r9 100 # Equals chi_r1*chi_r7/chi_r3

chi_r10 100 # Equals chi_r1*chi_r6/chi_r4

chi_r11 1000 # Equals chi_r1*chi_r7/chi_r5

R_dim0.025 # R_tot= 2*R_dim

S_tot0.05

end parameters

begin molecule types

R(DD,Y1~U~P,Y2~P)

S(NSH2~C~O,CSH2,PTP~C~O)

end molecule types

begin species

S(NSH2~C,CSH2,PTP~C)S_tot

# Pre-dimerized receptors

R(DD!1,Y1~U,Y2~P).R(DD!1,Y1~U,Y2~P) R_dim

end species

begin reaction rules

# Intra-complex phosphorylation

R(DD!+,Y1~U) -> R(DD!+,Y1~P) kkin_Y1

# Equilibrium between the closed form and open form of S

S(NSH2~C,PTP~C) <-> S(NSH2~O,PTP~O) kopen,kclose

# Binding of S(CSH2) from cytosol

R(Y2~P) + S(CSH2) <-> R(Y2~P!1).S(CSH2!1) kon_CSH2,koff_CSH2 \

exclude_reactants(2,R)

# Binding of S(NSH2~O) from cytosol

R(Y2~P) + S(NSH2~O) <-> R(Y2~P!1).S(NSH2~O!1) kon_NSH2,koff_NSH2 \

exclude_reactants(2,R)

# Binding of S(PTP~O) from cytosol

R(Y1~P) + S(PTP~O) <-> R(Y1~P!1).S(PTP~O!1) kon_PTP,koff_PTP \

exclude_reactants(2,R)

# Dephosphorylation of R(Y1~P)

R(Y1~P!1).S(PTP~O!1) -> R(Y1~U) + S(PTP~O) kcat_PTP

R(Y1~P!1).S(PTP~O!1) -> R(Y1~U).S(PTP~O) kcat_PTP

# 1 Intra-complex binding: CSH2 bound, association of NSH2 (open) with other receptor

R(Y2~P).S(NSH2~O,CSH2!+,PTP~O) <-> \

R(Y2~P!1).S(NSH2~O!1,CSH2!+,PTP~O) chi_r1*kon_NSH2,koff_NSH2

# 2 Intra-complex binding: CSH2 bound, association of PTP (open) with same receptor

R(Y1~P,Y2~P!1).S(NSH2~O,CSH2!1,PTP~O) <-> \

R(Y1~P!2,Y2~P!1).S(NSH2~O,CSH2!1,PTP~O!2) chi_r2*kon_PTP,koff_PTP

# 3 Intra-complex binding: CSH2 bound, association of PTP (open) with other receptor

R(Y1~P).R(Y2~P!1).S(NSH2~O,CSH2!1,PTP~O) <-> \

R(Y1~P!2).R(Y2~P!1).S(NSH2~O,CSH2!1,PTP~O!2) chi_r3*kon_PTP,koff_PTP

# 4 Intra-complex binding: NSH2 bound, association of CSH2 with other receptor

R(Y2~P).S(NSH2~O!+,CSH2,PTP~O) <-> \

R(Y2~P!1).S(NSH2~O!+,CSH2!1,PTP~O) chi_r1*kon_CSH2,koff_CSH2

# 5 Intra-complex binding: NSH2 bound, association of PTP with other receptor

R(Y1~P).R(Y2~P!1).S(NSH2~O!1,CSH2,PTP~O) <-> \

R(Y1~P!2).R(Y2~P!1).S(NSH2~O!1,CSH2,PTP~O!2) chi_r4*kon_PTP,koff_PTP

# 6 Intracomplex binding: NSH2 bound, association of PTP with same receptor

R(Y1~P,Y2~P!1).S(NSH2~O!1,CSH2,PTP~O) <-> \

R(Y1~P!2,Y2~P!1).S(NSH2~O!1,CSH2,PTP~O!2) chi_r5*kon_PTP,koff_PTP

# 7 Intra-complex binding: PTP bound, association of CSH2 with same receptor

R(Y1~P!1,Y2~P).S(NSH2~O,CSH2,PTP~O!1) <-> \

R(Y1~P!1,Y2~P!2).S(NSH2~O,CSH2!2,PTP~O!1) chi_r2*kon_CSH2,koff_CSH2

# 8 Intra-complex binding: PTP bound, association of CSH2 with other receptor

R(Y1~P!1).R(Y2~P).S(NSH2~O,CSH2,PTP~O!1) <-> \

R(Y1~P!1).R(Y2~P!2).S(NSH2~O,CSH2!2,PTP~O!1) chi_r3*kon_CSH2,koff_CSH2

# 9 Intra-complex binding: PTP bound, association of NSH2 with other receptor

R(Y1~P!1).R(Y2~P).S(NSH2~O,CSH2,PTP~O!1) <-> \

R(Y1~P!1).R(Y2~P!2).S(NSH2~O!2,CSH2,PTP~O!1) chi_r4*kon_NSH2,koff_NSH2

# 10 Intra-complex binding: PTP bound, association of NSH2 with same receptor

R(Y1~P!1,Y2~P).S(NSH2~O,CSH2,PTP~O!1) <-> \

R(Y1~P!1,Y2~P!2).S(NSH2~O!2,CSH2,PTP~O!1) chi_r5*kon_NSH2,koff_NSH2

# 11 Intra-complex binding: CSH2 & NSH2 bound, assoc. of PTP with same receptor as CSH2

R(Y1~P,Y2~P!1).R(Y2~P!2).S(NSH2~O!2,CSH2!1,PTP~O) <-> \

R(Y1~P!3,Y2~P!1).R(Y2~P!2).S(NSH2~O!2,CSH2!1,PTP~O!3) \

chi_r6*kon_PTP,koff_PTP

# 12 Intra-complex binding: CSH2 & NSH2 bound, assoc. of PTP with same receptor as NSH2

R(Y1~P,Y2~P!1).R(Y2~P!2).S(NSH2~O!1,CSH2!2,PTP~O) <-> \

R(Y1~P!3,Y2~P!1).R(Y2~P!2).S(NSH2~O!1,CSH2!2,PTP~O!3) \

chi_r7*kon_PTP,koff_PTP

# 13 Intra-complex binding: CSH2 & PTP bound to the same receptor, assoc. of NSH2

R(Y1~P!1,Y2~P!2).R(Y2~P).S(NSH2~O,CSH2!2,PTP~O!1) <-> \

R(Y1~P!1,Y2~P!2).R(Y2~P!3).S(NSH2~O!3,CSH2!2,PTP~O!1) \

chi_r8*kon_NSH2,koff_NSH2

# 14 Intra-complex binding: CSH2 & PTP bound to different receptors, assoc. of NSH2

R(Y2~P!1).R(Y1~P!2,Y2~P).S(NSH2~O,CSH2!1,PTP~O!2) <-> \

R(Y2~P!1).R(Y1~P!2,Y2~P!3).S(NSH2~O!3,CSH2!1,PTP~O!2) \

chi_r9*kon_NSH2,koff_NSH2

# 15 Intra-complex binding: PTP & NSH2 bound to different receptors, assoc. of CSH2

R(Y2~P!1).R(Y1~P!2,Y2~P).S(NSH2~O!1,CSH2,PTP~O!2) <-> \

R(Y2~P!1).R(Y1~P!2,Y2~P!3).S(NSH2~O!1,CSH2!3,PTP~O!2) \

chi_r10*kon_CSH2,koff_CSH2

# 16 Intra-complex binding: PTP & NSH2 bound to same receptor, assoc. of CSH2

R(Y1~P!1,Y2~P!2).R(Y2~P).S(NSH2~O!2,CSH2,PTP~O!1) <-> \

R(Y1~P!1,Y2~P!2).R(Y2~P!3).S(NSH2~O!2,CSH2!3,PTP~O!1) \

chi_r11*kon_CSH2,koff_CSH2

end reaction rules

begin observables

Molecules pYR R(Y1~P!?)

end observables

generate_network();

writeSBML();

simulate_ode({t_end=>1000,n_steps=>100,steady_state=>1,atol=>1e-10,rtol=>1e-12});